A group of 9-disubstituted fluorenes recently has been discovered to have potent antiarrhythmic activity; see U.S. Pat. Nos. 4,197,313 and 4,382,093. The 9-carbamoyl-9-aminoalkylfluorenes are among the most active compounds, and one compound within this group, namely 9-(3-isopropylaminopropyl)9-carbamoylfluorene hydrochloride, is now known generically as indecainide. The reported synthesis of the 9-carbamoyl-9-aminoalkylfluorenes have included acid hydrolysis of 9-cyano-9-aminoalkylfluorene, and more recently reductive alkylation of a 9-carbamoyl-9-cyanoalkylfluorene, see U.S. Pat. No. 4,282,170.
An object of the invention is to provide a process for the preparation of such 9-carbamoyl-9-aminoalkylfluorenes which is convenient to use, gives good yields and can be conducted under relatively mild conditions.
The invention provides a process for producing a compound of the formula ##STR1## wherein
R and R.sup.1 independently are hydrogen, C.sub.1 -C.sub.4 alkyl or halo;
R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl; and
R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 C.sub.2 -C.sub.5 alkenyl or phenyl C.sub.1 -C.sub.3 alkyl; or a salt thereof;
which comprises reacting a compound of the formula ##STR2## wherein
R and R.sup.1 are as defined above; and either R.sup.5 is --CONHR.sup.2 where R.sup.2 is as defined above and R.sup.6 is --(CH.sub.2).sub.2 CHO;
or R.sup.5 and R.sup.6, together, form the ring ##STR3## with an amine of the formula R.sup.4 NH.sub.2 and a reducing agent, or isolating an intermediate of the following formula from reaction of the compound of formula (II) with amine: ##STR4## where R.sup.7 is --CH(OH)NHR.sup.4 or --CH.dbd.NR.sup.4 and reducing the said intermediate.
The compounds of formula (II) are of two types: ##STR5## Such compounds are in fact interchangeable since reaction of base on compound (V) readily yields the aldehyde of formula (IV). In most systems an equilibrium between the two forms exists and the reactive species in the above process of the invention is probably always of formula (IV). Notwithstanding this both species can be employed in the reaction. Amine (R.sup.4 NH.sub.2) and reducing agent can be added simultaneously or the reducing agent added after reaction with amine.
The compounds of formula (III) are products of the reaction of amine with the compound of formula (II) and can be isolated and subsequently reacted with reducing agent. Often, however, it is preferable to avoid the extra step of isolating the intermediate product and to carry out the reaction in situ as described above.
In a further aspect of the invention compounds of formulae (II) can be prepared by a process which comprises reacting a compound of the formula ##STR6## with acrolein (CH.sub.2 .dbd.CHCHO) under basic conditions.
Thus the invention also provides a process for preparing a compound of formula (I) as defined above, which comprises
(a) reacting a compound of the formula ##STR7## wherein R, R.sup.1 and R.sup.2 are as defined above, with acrolein under basic conditions to provide a compound of formula ##STR8## wherein R.sup.5 and R.sup.6 are as defined above, and
(b) reacting the compound of formula (II) with an amine of the formula R.sup.4 NH.sub.2 and a reducing agent.